An effective LC-MS method for the simultaneous determination of a potential anti-rheumatoid arthritis drug, carboxyamidotriazole, and its major metabolite in rat plasma.

Carboxyamidotriazole (CAI) was previously recognized as a well-tolerated anticancer drug. It has also demonstrated significant anti-inflammatory effects in various cell and animal model experiments, prompting its investigation as a potential treatment for rheumatoid arthritis. In this study, the potential biotransformation metabolites of CAI were identified both in vitro and in vivo. A sensitive, specific, and accurate LC-MS method was developed for the quantitative analysis of CAI and its major metabolite, CAI-OH, in rat plasma. CAI, CAI-OH, and telmisartan (used as an internal standard) were separated using a Zorbax SB C18 column. The mobile phase consisted of water (phase A, containing 0.1% formic acid) and acetonitrile (phase B, containing 0.1% formic acid) at a flow rate of 0.2 mL/min. The analytes were examined using a high-resolution mass spectrometer, with detected mass-to-charge ratios of m/z 424.01293 for CAI, m/z 440.00785 for CAI-OH, and m/z 515.24415 for telmisartan. Good linearity was observed within the range of 10-5000 ng/mL. Both inter- and intra-batch precision (relative standard deviation, %) were below 6%, and the accuracy ranged from 94.9% to 106.1%. The analytes remained stable throughout the entire experimental period. This method was successfully applied in a pharmacokinetic study of CAI following oral administration in rats.

Detailed resume of S-methyltransferases: Categories, structures, biological functions and research advancements in related pathophysiology and pharmacotherapy.

Methylation is a vital chemical reaction in the metabolism of many drugs, neurotransmitters, hormones, and exogenous compounds. Among them, S-methylation plays a significant role in the biotransformation of sulfur-containing compounds, particularly chemicals with sulfhydryl groups. Currently, only three S-methyltransferases have been reported: thiopurine methyltransferase (TPMT), thiol methyltransferase (TMT), and thioether methyltransferase (TEMT). These enzymes are involved in various biological processes such as gene regulation, signal transduction, protein repair, tumor progression, and biosynthesis and degradation reactions in animals, plants, and microorganisms. Furthermore, they play pivotal roles in the metabolic pathways of essential drugs and contribute to the advancement of diseases such as tumors. This paper reviews the research progress on relevant structural features, metabolic mechanisms, inhibitor development, and influencing factors (gene polymorphism, S-adenosylmethionine level, race, sex, age, and disease) of S-methyltransferases. We hope that a better comprehension of S-methyltransferases will help to provide a reference for the development of novel strategies for related disorders and improve long-term efficacy.